Up to 20 million pregnant women in Africa receive intermittent presumptive treatment (IPTp) with the antimalarial sulfadoxine-pyrimethamine (SP) each year to prevent P. falciparum infection of the placenta;however, no one has studied the long term effects on their offspring. IPTp has been shown to reduce the incidence of placental malaria, severe maternal anemia, pre-term delivery, and increase mean birth weight, particularly during first and second pregnancy when women are most susceptible. Our preliminary studies indicate that IPTp selects for drug resistance alleles in placental infections, and that these resistance alleles are associated with increased risk of placental inflammation and low birth weight. Further, we find that IPTp is associated with an increased abundance of resistance alleles in the parasites infecting the offspring during infancy, and that infants exposed to IPTp in utero experience parasitemia at a younger age and more frequently throughout infancy. This project will examine the mechanisms that underlie these novel phenomena we have observed, and extend these to better understand the effects of IPTp on long term disease outcomes. In the mothers, we will assess whether inflammation related to resistant parasites also affects risk of maternal anemia, specifically by increasing IL-6 and hepcidin levels. In the children, we will examine whether IPTp increases risk of not only parasitemia, but also the risk of severe syndromes, including severe anemia and respiratory distress. We propose three alternative mechanisms by which IPTp might contribute to increased risk of disease: resistant parasites persist for a longer duration, leading to more severe clinical disease;resistant parasites increase inflammation, which is associated with severe malaria syndromes;resistant parasites are more virulent and grow to a higher density, a phenomenon known as competitive facilitation, which may result in increased clinical disease. We will examine these potential relationships using data and samples from a prospective delivery cohort of pregnant women and their offspring from Muheza, Tanzania who were followed for up to three years after delivery (2003-2006). We have a clinical database recording anemia and respiratory distress in women and infants, and we will relate this data to duration of infection using parasite genotyping, inflammation using cytokine and hepcidin measures, and parasite density. PUBLIC HEALTH RELEVANCE: Our observation that IPTp increases malaria risk in offspring creates an opportunity to better understand the mechanisms that may underlie risk of anemia and respiratory distress, two major killers in this population. Our proposed studies have important relevance for antimalarial policy affecting tens of millions of pregnant women.